FlyBase Allele Report: Hsap\GFAP[R79H.UAS]

General Information

Symbol

Hsap\GFAP^R79H.UAS

Species

H. sapiens

Name

FlyBase ID

FBal0283570

Feature type

allele

Associated gene

Hsap\GFAP

Associated Insertion(s)

Carried in Construct

P{UAS-hGFAP.R79H}

Also Known As

UAS-GFAP^R79H

Key Links

Transgenic product class

missense_variant

(Wang et al., 2011)

Mutagen

in vitro construct

Nature of the Allele

Transgenic product class

missense_variant

(Wang et al., 2011)

Mutagen

in vitro construct

(Wang et al., 2011)

Progenitor genotype

Carried in construct

P{UAS-hGFAP.R79H}

Cytology

Description

UAS regulatory sequences drive expression Hsap\GFAP coding sequences containing the R79H mutation linked to Alexander disease.

(Wang et al., 2011)

Allele components

Component

Use(s)

Regulatory region(s)

UAS

binary expression system - regulatory region

Encoded product / tool

Hsap\GFAP

Mutations Mapped to the Genome

Curation Data

Type

Location

Additional Notes

References

Variant Molecular Consequences

Associated Sequence Data

DDBJ / EMBL / GenBank

DNA sequence

Protein sequence

UniProtKB/Swiss-Prot

UniProtKB/TrEMBL

Expression Data

Reporter Expression

Additional Information

Statement

Reference

Marker for

Reflects expression of

Reporter construct used in assay

Human Disease Associations

Disease Ontology (DO) Annotations

Models Based on Experimental Evidence ( 1 )

Disease

Evidence

References

model of Alexander disease

CEA

(Olsen and Feany, 2019, Wang et al., 2016, Wang et al., 2015, Wang et al., 2011)

Modifiers Based on Experimental Evidence ( 1 )

Disease

Interaction

References

model of Alexander disease

is ameliorated by Nos^JF03220

(Wang et al., 2015)

is ameliorated by p53^11-1B-1

(Wang et al., 2015)

is exacerbated by Nos^UAS.cUa

(Wang et al., 2015)

is ameliorated by Nos^RNAi.UAS.cWa

(Wang et al., 2015)

is ameliorated by p53^JF02513

(Wang et al., 2015)

is ameliorated by GluRIIB^EGFP

(Wang et al., 2011)

is ameliorated by Hsap\SOD1^UAS.cWb

(Wang et al., 2011)

is exacerbated by Catⁿ¹

(Wang et al., 2011)

is ameliorated by Hsp26^UAS.cWa

(Wang et al., 2011)

is ameliorated by Cat^UAS.cAa

(Wang et al., 2011)

is ameliorated by Hsp27^UAS.cWa

(Wang et al., 2011)

is exacerbated by Sod1ⁿ¹

(Wang et al., 2011)

is ameliorated by Hsap\HSPA1A^UAS.cWa

(Wang et al., 2011)

is ameliorated by mAChR-A^GD630

(Wang et al., 2016)

is ameliorated by mAChR-A^KK109077

(Wang et al., 2016)

Comments on Models/Modifiers Based on Experimental Evidence ( 0 )

Disease-implicated variant(s)

This allele represents a human variant implicated in disease.

(Wang et al., 2011)

GFAP:p.Arg79His

(FlyBase curators, 2019-)

Variants Synonym(s)

Associated human disease model(s)

Alexander disease

External database links

ClinVar: GFAP_16170

Comments concerning this variant

Phenotypic Data

Phenotypic Class

abnormal neuroanatomy | adult stage, with Scer\GAL4^alrm.PD

(Wang et al., 2015)

abnormal neuroanatomy | adult stage, with Scer\GAL4^Mz709

(Wang et al., 2015)

abnormal neuroanatomy | adult stage, with Scer\GAL4^repo.PU

(Wang et al., 2015)

bang sensitive, with Scer\GAL4^repo.PU

(Wang et al., 2015)

increased cell death | adult stage, with Scer\GAL4^repo.PU

(Wang et al., 2015)

increased cell death | adult stage | cell non-autonomous, with Scer\GAL4^repo.PU

(Wang et al., 2015)

increased cell death | progressive, with Scer\GAL4^repo

(Wang et al., 2011)

paralytic, with Scer\GAL4^repo

(Wang et al., 2011)

Phenotype Manifest In

adult brain, with Scer\GAL4^repo.PU

(Wang et al., 2015)

adult brain, with Scer\GAL4^repo

(Wang et al., 2011)

adult CNS glial cell, with Scer\GAL4^alrm.PD

(Wang et al., 2015)

adult CNS glial cell, with Scer\GAL4^Mz709

(Wang et al., 2015)

adult CNS glial cell, with Scer\GAL4^repo.PU

(Wang et al., 2015)

lamina, with Scer\GAL4^repo

(Wang et al., 2011)

neuron | adult stage | cell non-autonomous, with Scer\GAL4^repo.PU

(Wang et al., 2015)

neuron | cell non-autonomous, with Scer\GAL4^repo

(Wang et al., 2011)

Detailed Description

Statement

Reference

Over-expression of Hsap\GFAP^{R79H.Scer\UAS} driven in glia by Scer\GAL4^repo.PU, Scer\GAL4^alrm.PD or Scer\GAL4^Mz709 leads to Rosenthal fiber-like inclusion formations in 20 day old flies; flies with expression of Hsap\GFAP^{R79H.Scer\UAS} driven by Scer\GAL4^repo.PU show increases in cell death in the brain and increases in seizure frequency.

Over-expression of Hsap\GFAP^{R79H.Scer\UAS} driven in glia by Scer\GAL4^repo.PU leads to increased cell death in both glia and neurons (cell non-autonomous neurodegeneration).

(Wang et al., 2015)

Expression of Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo does not affect developmental rate or eclosion. Overall brain structure appears normal at 1 day of age, as assayed by haematoxylin and eosin. A TUNEL assay for apoptotic cells does not reveal dying cells at 1 day after eclosion. However, increasing numbers of TUNEL-positive cells are seen as the animals age, indicating severe toxicity. The TUNEL-positive cells are widespread, with no obvious predilection for particular areas of the brain. In the lamina, there is a trend towards decreased numbers of glial cells with advancing age and a significant loss of neurons at 10 and 20 days of age, consistent with a non-autonomous effect.

Expression of Hsap\GFAP^{R79H.Scer\UAS} in glial under the control of Scer\GAL4^repo promotes the loss of GluRIIB-expressing neurons which is particularly apparent by 20 days after eclosion.

Flies expressing Hsap\GFAP^{R79H.Scer\UAS} in glial under the control of Scer\GAL4^repo exhibit a significantly increased frequency of seizures in response to mechanical stimulation (with more frequency than in Hsap\GFAP^Scer\UAS.cWa mutants).

Flies expressing Hsap\GFAP^{R79H.Scer\UAS} in glial under the control of Scer\GAL4^repo display abnormal protein aggregation, with numerous eosinophilic, elongated and beaded inclusions. These inclusions are present within the cytoplasm of glial cells, as recognised by their characteristic electron-dense cytoplasm. Inclusions are oesinophilic and granular and not membrane bound. Inclusions are present in a widespread pattern throughout the neuropil and cortex. Inclusions are found in 1 day old flies expressing Hsap\GFAP^{R79H.Scer\UAS}. Significant additional accumulation of inclusion bodies occurs by 10 and 20 days of age.

Flies expressing Hsap\GFAP^{R79H.Scer\UAS} in glial under the control of Scer\GAL4^repo display an increase in autophagy induction with age, with a modest induction present at 1 day after eclosion and more substantial induction at 10 and 20 days of age.

(Wang et al., 2011)

External Data

Linkouts

Interactions

Show genetic interaction network for Enhancers & Suppressors

Phenotypic Class

Enhanced by

Statement

Reference

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage phenotype, enhanceable by Nos^UAS.cUa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has bang sensitive phenotype, enhanceable by Nos^UAS.cUa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage | cell non-autonomous phenotype, enhanceable by Nos^UAS.cUa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Suppressed by

Statement

Reference

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | cell non-autonomous | adult stage phenotype, suppressible by Nos^JF03220, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | cell non-autonomous | adult stage phenotype, suppressible by Nos^RNAi.UAS.cWa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage phenotype, suppressible by p53^JF02513, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has bang sensitive phenotype, suppressible by p53^JF02513, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage phenotype, suppressible by p53^11-1B-1

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage phenotype, suppressible by Nos^JF03220, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has bang sensitive phenotype, suppressible by Nos^JF03220, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has increased cell death | adult stage phenotype, suppressible by Nos^RNAi.UAS.cWa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has bang sensitive phenotype, suppressible by Nos^RNAi.UAS.cWa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Phenotype Manifest In

Enhanced by

Statement

Reference

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has adult brain phenotype, enhanceable by Nos^UAS.cUa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has neuron | adult stage | cell non-autonomous phenotype, enhanceable by Nos^UAS.cUa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Suppressed by

Statement

Reference

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has adult brain phenotype, suppressible by Nos^JF03220, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has adult brain phenotype, suppressible by Nos^RNAi.UAS.cWa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has neuron | cell non-autonomous | adult stage phenotype, suppressible by Nos^JF03220, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has neuron | cell non-autonomous | adult stage phenotype, suppressible by Nos^RNAi.UAS.cWa, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has adult brain phenotype, suppressible by p53^JF02513, Scer\GAL4^repo.PU

(Wang et al., 2015)

Hsap\GFAP^R79H.UAS, Scer\GAL4^repo.PU has adult brain phenotype, suppressible by p53^11-1B-1

(Wang et al., 2015)

Additional Comments

Genetic Interactions

Statement

Reference

Xenogenetic Interactions

Statement

Reference

Co-expression of Nos^Scer\UAS.cUa significantly enhances cell death (in both glia and non-autonomously in neurons) and seizure frequency in flies with expression of Hsap\GFAP^{R79H.Scer\UAS} driven by Scer\GAL4^repo.PU. Co-expression of Nos^JF03220 or Nos^{dsRNA.shRNA.Scer\UAS} significantly suppresses cell death (in both glia and non-autonomously in neurons) and seizure frequency in flies with expression of Hsap\GFAP^{R79H.Scer\UAS} driven by Scer\GAL4^repo.PU.

Pharmacological inhibition of Nos through feeding of L-name (compared to no effect seen with feeding of the inactive enantiomer, D-name) decreases cell death and seizure frequency in flies with expression of Hsap\GFAP^{R79H.Scer\UAS} driven by Scer\GAL4^repo.PU.

Co-expression of p53^JF02513 significantly suppresses cell death and seizure frequency in flies with expression of Hsap\GFAP^{R79H.Scer\UAS} driven by Scer\GAL4^repo.PU; p53^11-1B-1 significantly suppresses cell death.

(Wang et al., 2015)

Overexpression of l(2)efl^Scer\UAS.cWa in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of l(2)efl^Scer\UAS.cWa also decreases the number of seizures. Protection from cellular toxicity is accompanied by a significant reduction in the number of inclusion bodies and in activation of autophagy.

Overexpression of Hsp26^Scer\UAS.cWa in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of Hsp26^Scer\UAS.cWa also decreases the number of seizures. Protection from cellular toxicity is accompanied by a significant reduction in the number of inclusion bodies.

Overexpression of Hsp27^Scer\UAS.cWa in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of Hsp27^Scer\UAS.cWa also decreases the number of seizures. Protection from cellular toxicity is accompanied by a significant reduction in the number of inclusion bodies.

Overexpression of Cat^Scer\UAS.cAa in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of Cat^Scer\UAS.cAa also decreases the number of seizures. Protection from cellular toxicity does not alter the number of inclusion bodies.

A Catⁿ¹ heterozygous background significantly enhances Hsap\GFAP^{R79H.Scer\UAS} toxicity and increases the frequency of mechanically-stimulated seizures in these flies. An increase in cellular toxicity does not alter the number of inclusion bodies but does increase autophagy induction.

A Sodⁿ¹ heterozygous background significantly enhances Hsap\GFAP^{R79H.Scer\UAS} toxicity and increases the frequency of mechanically-stimulated seizures in these flies. Protection from cellular toxicity does not alter the number of inclusion bodies. An increase in cellular toxicity does not alter the number of inclusion bodies but does increase autophagy induction.

Overexpression of Hsap\HSPA1A^Scer\UAS.cWa in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of Hsap\HSPA1A^Scer\UAS.cWa also decreases the number of seizures. Protection from cellular toxicity is accompanied by a significant reduction in the number of inclusion bodies and in activation of autophagy.

Overexpression of Hsap\SOD1^Scer\UAS.cWb in flies expressing Hsap\GFAP^{R79H.Scer\UAS} under the control of Scer\GAL4^repo results in a significant reduction in cell death. In addition, expression of Hsap\SOD1^Scer\UAS.cWb also decreases the number of seizures. Protection from cellular toxicity does not alter the number of inclusion bodies.

Expression of Eaat1^Scer\UAS.cRa significantly suppresses the Hsap\GFAP toxicity, but does not influence inclusion formation, Hsap\GFAP solubility or autophagy induction.

(Wang et al., 2011)

Complementation and Rescue Data

Comments

Images (0)

Mutant

Wild-type

Stocks (0)

Notes on Origin

Discoverer

External Crossreferences and Linkouts ( 0 )

Synonyms and Secondary IDs (2)

Reported As

Symbol Synonym

Hsap\GFAP^{R79H.Scer\UAS}

Hsap\GFAP^R79H.UAS

Name Synonyms

Secondary FlyBase IDs

References (7)

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